DESCRIPTION(adapted from applicant's abstract): Neurons communicate with each other through synaptic transmission. Changes in the effectiveness of synapses underlie the ability of neuronal networks to store and retrieve information, the cellular representation of learning and memory. One form of synaptic plasticity is facilitation, a phenomenon by which synapses becomes transiently more effective following repeated use. Facilitation is a ubiquitous phenomenon observed at many synapses and represents a very general process controlling the effectiveness of synapses. This application addresses the question of what mechanisms operate within the synaptic terminal to allow secretion to increase with increased rates of use. The fundamental event in synaptic transmission is the entry of calcium into the synaptic terminal during an action potential, leading to the fusion of a synaptic vesicle with the terminal membrane. The classical interpretation of facilitation was repetitive nerve stimulation increases the Ca++ concentration at presynaptic release sites, which in turn increases the probability of each vesicle to be released. Recently it was demonstrated that the number of synaptic vesicles properly activated to be released (the releasable pool of quanta) is highly dynamic and has a critical role in synaptic plasticity. The goal of the proposed work is to develop and test a quantitative model of neurosecretion, which will clarify the role of the increase in residual calcium, activation of release sites and the increase in the releasable pool of quanta and thereby account for presynaptic facilitation. Facilitation has strictly distinguishable components: short-term facilitation (STF) and long-term facilitation (LTF), which results from different underlying mechanisms. The proposed work will take advantage of the separation of these two components to distinguish between different mechanisms. Experiments will test the hypothesis that STF is determined by an increase of intracellular calcium and vesicle mobilization, while LTF is additionally controlled by activation of previously silent release sites. The approach is to combine computer simulations of presynaptic processes with electrophysiological detection of the number of released vesticles.